The present invention, in some embodiments thereof, relates to regulation of Amyloid-β (Aβ) molecular composition for the treatment of Alzheimer's disease (AD).
Alzheimer's disease (AD) is the most common form of both senile and presenile dementia in the world and is recognized clinically as relentlessly progressive loss of memory and intellectual function and disturbances in speech (Merritt, 1979, A Textbook of Neurology, 6th edition, pp. 484-489, Lea & Febiger, Philadelphia, which is incorporated herein by reference). Alzheimer's disease begins with mildly inappropriate behavior, uncritical statements, irritability, a tendency towards grandiosity, euphoria, and deteriorating performance at work; it progresses through deterioration in operational judgment, loss of insight, depression, and loss of recent memory; and it ends in severe disorientation and confusion, apraxia of gait, generalized rigidity, and incontinence (Gilroy & Meyer, 1979, Medical Neurology, pp. 175-179, MacMillan Publishing Co., which is incorporated herein by reference. Alzheimer's disease is found in about 10% of the population over the age of 65 and 47% of the population over the age of 85 (Evans et al., 1989, JAMA, 262:2551-2556, which is incorporated herein by reference).
It has been widely accepted that the accumulation of amyloid-β (Aβ) peptides in the brain extracellular space and alteration in Aβ molecular composition are critical for developing synaptic and cognitive deficits in Alzheimer's disease (AD). Aβ is produced by sequential limited proteolysis of the amyloid precursor protein (APP) by two aspartyl proteases, β- and γ-secretases. Proteolysis by γ-secretase is the last processing step resulting release of Aβ. Normally, γ-secretase cleavage results in 40 amino acids in length Aβ peptides (Aβ40) and smaller amount of longer, 42 amino acid species (Aβ42). Aβ42 exhibits faster rate of amyloid formation and has been proposed to “seed” Aβ40 aggregation. Small alterations in the molecular composition of Aβ, reflected by the Aβ42/40 ratio, can dramatically affect Aβ aggregation kinetics, the morphology of amyloid fibrils and synaptic function.
Elucidating factors that regulate the Aβ42/40 ratio levels is important for understanding AD pathogenesis. Genetic studies provide overwhelming evidence that mutations in genes encoding human amyloid-precursor protein (hAPP), presenilin 1 (PS1) or presenilin 2 (PS2) are associated with early-onset autosomal dominant familial AD (FAD). Many of FAD mutations trigger Aβ oligomerization and subsequent aggregation through relative over-production of Aβ42 isoform with resultant increase in the Aβ42/40 ratio. However, FAD mutations account only for 1-2% of AD cases, thus leaving the physiological mechanisms that trigger experience-dependent Aβ42/40 alternations in the most common, late-onset sporadic AD an enigma.
The use of electrical stimulation for treating neurological disease, including such disorders as movement disorders including Parkinson's disease, essential tremor, dystonia, and chronic pain, has been widely discussed in the literature. It has been recognized that electrical stimulation holds significant advantages over lesioning since lesioning destroys the nervous system tissue. In many instances, the preferred effect is to modulate neuronal activity. Electrical stimulation permits such modulation of the target neural structures and, equally importantly, does not require the destruction of nervous tissue. Such electrical stimulation procedures include electroconvulsive therapy (ECT), repetitive transcranial (rTMS) magnetic stimulation and vagal nerve stimulation (VNS).
Deep brain stimulation (DBS) has been applied to the treatment of central pain syndromes and movement disorders, and it is currently being explored as a therapy for epilepsy. For instance, U.S. Pat. Nos. 6,016,449 and 6,176,242 disclose a system for the electrical stimulation of areas in the brain for the treatment of certain neurological diseases such as epilepsy, migraine headaches and Parkinson's disease.
Ferrucci et al [Neurology, 2008, Vol 71, Pages 493-498] teaches that transcranial direct current stimulation (tDCS) over the temporoparietal areas in patients with Alzheimer disease improved recognition memory.
U.S. Patent Application No. 2006/0212090 teaches electrical stimulation of various areas of the brain including the hippocampus for the treatment of Alzheimer's.
Chronic electrical stimulation of the hippocampus for the treatment of Alzheimer's disease has now reached phase II clinical trials [Annals of Neurology, Vol. 68, Issue 4, pages 521-534].
Additional background art includes U.S. Patent Application Nos: 20090287035, 20090105521, 20090099623, 20080227139, 20070135860, 20050021103 and U.S. Pat. No. 7,603,174.